{"601743":{"#nid":"601743","#data":{"type":"news","title":"Hatchet Enzyme, Enabler of Sickness and of Health, Exposed by Neutron Beams","body":[{"value":"\u003Cp\u003ETucked away inside cell membranes, a molecular butcher does the bidding of healthy cells but also of disease agents. It has been operating out of clear view, but researchers just shined a mighty spotlight on it.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EThe butcher is a common enzyme called presenilin, which chops lengthy protein building blocks down to useable shorter lengths. It resides in membrane spaces that evade ready experimental detection, but\u0026nbsp;\u003Ca href=\u0022http:\/\/www.cell.com\/biophysj\/fulltext\/S0006-3495(17)35097-X\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003Ein a new study, researchers\u003C\/a\u003E\u0026nbsp;at the Georgia Institute of Technology and Oak Ridge National Laboratory (ORNL) have illuminated\u0026nbsp;\u003Ca href=\u0022https:\/\/en.wikipedia.org\/wiki\/Presenilin\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003Epresenilin\u003C\/a\u003E\u0026nbsp;using a neutron beam produced by the world\u0026#39;s most powerful research nuclear reactor.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EPresenilin is one of many mysterious protein structures residing in our cell membranes, where they are essential to life.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;One-third of our genome goes to work to encode intramembrane proteins,\u0026rdquo; said\u0026nbsp;\u003Ca href=\u0022http:\/\/www.chemistry.gatech.edu\/faculty\/lieberman\/\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003ERaquel Lieberman, an associate professor\u003C\/a\u003E\u0026nbsp;in Georgia Tech\u0026rsquo;s School of Chemistry and Biochemistry. \u0026ldquo;Some of them are huge and do super complex biochemistry.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003EPresenilin is an enzyme, more particularly an\u0026nbsp;\u003Ca href=\u0022https:\/\/en.wikipedia.org\/wiki\/Intramembrane_protease\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003Eintramembrane protease\u003C\/a\u003E. There are four classes of these, and they are needed, among other things, for: Alerting to and defending against infectors, and cell differentiation and development.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EIf the latter two go wrong, that can lead to cancer.\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003EGrainy neutron mugshot\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003ENow, the researchers have gotten their first figurative mugshot of an intramembrane protein, the presenilin. Technically speaking, the researchers worked with a presenilin cousin found in microbes --\u0026nbsp;\u003Cem\u003EM. marisnigri\u003C\/em\u003E\u0026nbsp;intramembrane aspartyl protease or MmIAP -- but here we will use presenilin and MmIAP interchangeably for simplicity\u0026rsquo;s sake.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EThe measurement was low-resolution but revealed enough to establish that the protein structure is more simply put together than previously believed, and that surprised the scientists.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;Our sample shows that this is\u0026nbsp;\u003Ca href=\u0022https:\/\/en.wikipedia.org\/wiki\/Protein_quaternary_structure\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003Ea monomer all by itself,\u0026rdquo; Lieberman said. \u0026ldquo;We were expecting a dimer or a trimer\u003C\/a\u003E.\u0026rdquo; That means it was made up of one long strand, mostly coiled up like a spring, instead of doubled-up or tripled-up curly strands.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EPresenilin (MmIAP) is armed with two chemical knives,\u0026nbsp;\u003Ca href=\u0022https:\/\/en.wikipedia.org\/wiki\/Aspartic_acid\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003Easpartates\u003C\/a\u003E, that reliably make cuts on peptides,\u0026nbsp;subunits that make up proteins.\u0026nbsp;\u003Ca href=\u0022http:\/\/www.jbc.org\/content\/early\/2018\/01\/30\/jbc.RA117.001436.abstract\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003EAnd a second new study\u003C\/a\u003E\u0026nbsp;by the same researchers illuminated how the cleaving works.\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003EAnybody\u0026rsquo;s peptide butcher\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003EPresenilin can trim peptides into building blocks helpful to its own cells, or whittle bad peptide chunks that end up in amyloid-beta plaque, a suspect in\u0026nbsp;\u003Ca href=\u0022http:\/\/www.rh.gatech.edu\/features\/alzheimers-killing-mind-first\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003EAlzheimer\u0026rsquo;s disease\u003C\/a\u003E. Or presenilin can aid and abate\u0026nbsp;\u003Ca href=\u0022https:\/\/www.mayoclinic.org\/diseases-conditions\/hepatitis-c\/symptoms-causes\/syc-20354278\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003Ehepatitis C\u003C\/a\u003E\u0026nbsp;viruses by carving components it needs to reproduce.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EUnderstanding how presenilin works could one day prove useful to medical research. \u0026ldquo;If you could find a way to interfere with it selectively, you could stop the spread of hepatitis C in the body,\u0026rdquo; Lieberman said.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EThe researchers, led by Lieberman and neutron scattering scientist\u0026nbsp;\u003Ca href=\u0022https:\/\/neutrons.ornl.gov\/contacts\/urbanvs\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003EVolker Urban from ORNL\u003C\/a\u003E, published the revelations of the neutron scattering\u0026nbsp;\u003Ca href=\u0022http:\/\/www.cell.com\/biophysj\/fulltext\/S0006-3495(17)35097-X\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003Eon February 6, 2018, in\u0026nbsp;\u003Cem\u003EBiophysical Journal\u003C\/em\u003E\u003C\/a\u003E. The new insights into presenilin functioning are to officially publish in March\u0026nbsp;\u003Ca href=\u0022http:\/\/www.jbc.org\/content\/early\/2018\/01\/30\/jbc.RA117.001436.abstract\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003Ein the\u003Cem\u003E\u0026nbsp;Journal of Biological Chemistry\u003C\/em\u003E\u0026nbsp;but the study is currently available online without embargo\u003C\/a\u003E. First authors were Swe-Htet Naing of Georgia Tech and Ryan Oliver of Oak Ridge.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EResearch was funded by the National Science Foundation, the National Institutes of Health, and the U.S. Department of Energy.\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003EHerding hydrophobic hiders\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003EBy going to the High Flux Isotope Reactor (HFIR), the scientists were reaching for the big gun\u0026nbsp;to make presenilin (MmIAP) come out of hiding.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EHFIR\u0026rsquo;s neutron beams were cooled to minus 253 degrees Celsius (minus 424 degrees Fahrenheit) to slow the neutrons down, so they could probe molecular features of the biological samples.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EPresenilin and other intramembrane proteins warrant such proverbial desperate measures. They live in a lipid environment and hate water about the way cats do, and that\u0026rsquo;s a problem for researchers studying them.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;When you have proteins that are not soluble in water, you\u0026rsquo;re in trouble,\u0026rdquo; Lieberman said. \u0026ldquo;The usual techniques to analyze them become very, very difficult, if not impossible. And when you chemically bootstrap these proteins to be able use these water-soluble methods, you have really poor chances of seeing the protein\u0026rsquo;s actual structure that performs its function.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003EForm follows function\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003EImages derived from water-based analytical methods in Lieberman\u0026rsquo;s lab have not completely jibed with presenilin\u0026rsquo;s function. For one, the enzyme\u0026rsquo;s cutting surfaces have been too far apart. The neutron beam\u0026rsquo;s revelations indicated a form that seemed more logical.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;Our shape was tighter, and made more sense with presenilin\u0026rsquo;s function in its natural setting in the membrane,\u0026rdquo; Lieberman said.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EThe presenilin (MmIAP) samples examined at the HFIR were suspended in a solution friendly to the\u0026nbsp;\u003Ca href=\u0022https:\/\/www.gbiosciences.com\/Educational-Products\/Hydrophobic-Hydrophilic-Proteins\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003Ehydrophobic protein\u003C\/a\u003E. Ironically, presenilin and other intramembrane proteases often\u0026nbsp;\u003Ca href=\u0022https:\/\/en.wikipedia.org\/wiki\/Hydrolysis\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003Ehydrolyze\u0026nbsp;\u003C\/a\u003Epeptides, in other words, they add water to them.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;These proteases are confined to the lipid cell membrane where there is no water. Since water is required for hydrolysis, it has to come from outside the membrane,\u0026rdquo; Lieberman said. \u0026ldquo;How that happens is yet another mystery that needs uncovering.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Ch4\u003E\u003Cstrong\u003ERobust, reliable cleavers\u003C\/strong\u003E\u003C\/h4\u003E\r\n\r\n\u003Cp\u003EThe precision and consistency, with which the presenilin\u0026nbsp;\u003Ca href=\u0022https:\/\/www.merriam-webster.com\/dictionary\/homologous\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003Ehomologue\u003C\/a\u003E\u0026nbsp;MmIAP cleaved peptides, impressed the researchers.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;When we used a model synthetic peptide, it cleaved only at very specific positions on the peptide,\u0026rdquo; Lieberman said. \u0026ldquo;When we switched to a real biological peptide, it also cleaved very exactly.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003EThe researchers put the presenilin through various mutations, which had little to no effect on its cleaving abilities. That could mean that its baseline functioning is nearly immune to genetic interference.\u003C\/p\u003E\r\n\r\n\u003Cp\u003EOn a chilling note, when the researchers observed the microbial presenilin cousin, MmIAP, cutting amyloid-beta precursor peptides, it always made the chop in a way notorious for amyloid\u0026rsquo;s association with\u0026nbsp;\u003Ca href=\u0022http:\/\/www.rh.gatech.edu\/features\/alzheimers-killing-mind-first\u0022 rel=\u0022noopener noreferrer\u0022 target=\u0022_blank\u0022\u003EAlzheimer\u0026rsquo;s disease\u003C\/a\u003E.\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u0026ldquo;We never saw the cut that made what is typically viewed as the \u0026lsquo;good\u0026rsquo; amyloid, A-beta-40,\u0026rdquo; Lieberman said. \u0026ldquo;We only saw cuts that led to the \u0026lsquo;bad\u0026rsquo; amyloid, A-beta-42.\u0026rdquo;\u003C\/p\u003E\r\n\r\n\u003Cp\u003EMore research would be needed to explain why that happened; if the same is true for presenilin in human cell membranes, and also if some regulator prevents the creation or accumulation of so much bad amyloid in healthy cells.\u003C\/p\u003E\r\n\r\n\u003Cp\u003ELike this article?\u0026nbsp;\u003Ca href=\u0022http:\/\/www.rh.gatech.edu\/subscribe\u0022 target=\u0022_blank\u0022\u003EGet our email newsletter here.\u003C\/a\u003E\u003C\/p\u003E\r\n\r\n\u003Cp\u003EAlso READ: \u003Ca href=\u0022http:\/\/www.rh.gatech.edu\/features\/alzheimers-killing-mind-first\u0022 target=\u0022_blank\u0022\u003EAlzheimer\u0026#39;s: Killing the Mind First\u003C\/a\u003E\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Cem\u003EKevin Weiss from Oak Ridge National Laboratory coauthored the study in Biophysical Journal. Sibel Kalyoncu, David Smalley, Hyojung Kim, Xingjian Tao, Josh George, Alex Jonke, Ryan Oliver, and Matthew Torres coauthored the study in the Journal of Biological Chemistry. Research was funded by the National Science Foundation\u0026rsquo;s Division of Molecular and Cellular Biosciences (grant 0845445), and the National Institutes of Health (grant R01GM112662 and R01GM118744). Neutron scattering research conducted at the Bio-SANS instrument, a DOE Office of Science, Office of Biological and Environmental Research resource, used resources at the High Flux Isotope Reactor, a DOE Office of Science, Scientific User Facility operated by the Oak Ridge National Laboratory.\u003C\/em\u003E\u0026nbsp;\u003Cem\u003EAny opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the sponsors.\u003C\/em\u003E\u003C\/p\u003E\r\n","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003EA pioneering glimpse\u0026nbsp;inside elusive cell membranes illuminates a player in cell health but also in hepatitis C and in Alzheimer\u0026#39;s. With the most powerful research neutron beams in the country, researchers open a portal into the hidden world of intramembrane proteins, which a third of the human genome is required to create.\u003C\/p\u003E\r\n","format":"limited_html"}],"field_summary_sentence":[{"value":"A pioneering glimpse inside elusive cell membranes exposes a major player in cell health but also in hepatitis C and in Alzheimer\u0027s."}],"uid":"31759","created_gmt":"2018-02-01 21:59:53","changed_gmt":"2018-02-12 14:51:52","author":"Ben Brumfield","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2018-02-06T00:00:00-05:00","iso_date":"2018-02-06T00:00:00-05:00","tz":"America\/New_York"},"extras":[],"hg_media":{"601735":{"id":"601735","type":"image","title":"High Flux Isotope Reactor, most powerful of its kind in the world","body":null,"created":"1517520012","gmt_created":"2018-02-01 21:20:12","changed":"1517520012","gmt_changed":"2018-02-01 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(404-660-1408)\u003C\/p\u003E\r\n\r\n\u003Cp\u003E\u003Cstrong\u003EGeorgia Institute of Technology\u003Cbr \/\u003E\r\n177 North Avenue\u003Cbr \/\u003E\r\nAtlanta, Georgia \u0026nbsp;30332-0181 \u0026nbsp;USA\u003C\/strong\u003E\u003C\/p\u003E\r\n","format":"limited_html"}],"email":["ben.brumfield@comm.gatech.edu"],"slides":[],"orientation":[],"userdata":""}}}